Prevention of type 2 diabetes by dietary protein restriction

• Applicant: Privatdozent Dr. Thomas Laeger
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 339790145

• Final Report Year: 2022

Final Report Abstract

Our data suggest that protein restriction protects against obesity and improves glucose homeostasis in the context of diet-induced obesity via FGF21-dependent mechanisms (in the brain) that are different from dietary (calorie) restriction. Given that endogenous FGF21 is improving the glucose homeostasis, we investigated whether it is also preventing the onset of type 2 diabetes in the New Zealand Obese mouse – a model for polygenic obesity and diabetes. At first, we ruled out that the NZO mouse is FGF21-resistant. Under high-carbohydrate feeding, exogenous treatments of FGF21 to NZO mice prevented islet destruction and hyperglycemia, improved glucose clearance without changes in total fat mass. As such, these data support the diabetes-prone NZO mouse as a potential animal model to study endogenous FGF21 actions in regard to the prevention of diabetes. In short, in NZO mice, prevention from hyperglycemia through protein restriction is compromised by high dietary carbohydrates despite increased FGF21 levels and does not require body fat loss but increased hepatic long-chain ceramides. Thus, increased FGF21 levels (and elevated energy expenditure) are not protecting from hyperglycemia per se. Since our data showed a dietary protein-dependent regulation of hepatic DPP4, which is inactivating incretins, the reduction of DDP4 levels under a protein-restricted feeding regimen might contribute to the prevention of hyperglycemia. As is generally known, the restriction of a single essential amino acid, namely methionine, is also increasing circulating FGF21 levels. Our data demonstrated in NZO mice that a dietary methionine restriction, without a decrease in protein content, was preventing the onset of hyperglycemia and β-cell loss as well. When cystine was added to a methionine-restricted diet, FGF21 levels were not increased and the glucose homeostasis was not improved, which demonstrated that FGF21 was responsible for the beneficial effects of a dietary methionine restriction. Interestingly, human plasma FGF21 levels were significantly higher in vegans compared to omnivores (presumably due to the lower methionine intake), and a short-term switch to a vegetarian diet for four days was increasing plasma FGF21 in humans. Thus, a restriction of dietary methionine may be a beneficial nutritional strategy in patients at high risk of developing type 2 diabetes. However, long-term protein restriction leads to the deterioration of bone microarchitecture, which is mediated by FGF21. The increased levels of FGF21 observed in vegans and vegetarians may therefore explain the lower, but clinically insignificant, bone mineral density. Collectively, these data fundamentally redefine the physiological roles of FGF21 while also identifying a previously undescribed mechanism for the detection of protein restriction. Our data suggest that liver-derived FGF21 is, in fact, a ‘protein sensing signal’ which acts on the brain to regulate metabolism in the protein-dependent state. So far, FGF21 may be the first hormone that specifically acts as a signal of dietary protein. The protein and methionine-restricted induction of FGF21 seems to be universally given that it occurs in rodents (rats and different mice strains) as well as in humans. Increased FGF21 levels in vegans may contribute to the normoglycemic phenotype. Taken together, these studies provide a better understanding of the physiology of FGF21 action as a whole and establish a completely new mechanism to explain a fundamental aspect of biology, as defined by the detection of restricted dietary protein and its adaptive responses.

Publications

• FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes. Diabetologia 2017; 60(11): 2274-2284
  Laeger T, Baumeier C, Wilhelmi I, Würfel J, Kamitz A, and Schürmann A
  
• Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes. Diabetologia 2018; 61(6): 1459-1469
  Laeger T, Castaño-Martinez T, Werno MW, Japtok L, Baumeier C, Jonas W, Kleuser B, and Schürmann A
  
• The protein paradox – how much dietary protein is good for health? Ernahrungs Umschau 2018; 65(2): 42-47
  Klaus S, Pfeiffer AFH, Boeing H, Laeger T, and Grune T
  
• Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein. J Nutr Biochem 2019; 63: 109-116
  Saussenthaler S, Ouni M, Baumeier C, Schwerbel K, Gottmann P, Christmann S, Laeger T, and Schürmann A
  
• FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism. Cell Rep 2019; 27(10): 2934-2947
  Hill CM, Laeger T, Dehner M, Albarado DC, Clarke B, Wanders D, Burke SJ, Collier JJ, Qualls-Creekmore E, Solon-Biet S, Simpson SJ, Berthoud HR, Münzberg H, and Morrison CD
  
• FGF21, not GCN2, influences bone morphology due to dietary protein restriction. Bone Rep 2019; 12: 100241
  McNulty MA, Goupil BA, Albarado DC, Castaño-Martinez T, Ambrosi TH, Puh S, Schulz TJ, Schürmann A, Morrison CD, and Laeger T
  
• Methionine restriction prevents onset of type 2 diabetes in NZO mice. FASEB J 2019; 33(6): 7092-7102
  Castaño-Martinez T, Schumacher F, Schumacher S, Kochlik B, Weber D, Grune T, Biemann R, McCann A, Abraham K, Weikert C, Kleuser B, Schürmann A, and Laeger T
  
• (2022). Organ cross-talk regulates (brain) insulin action. In A. Kleinridders (Ed.) Physiological Consequences of Brain Insulin Action. CRC Press. ISBN 9780367529482
  Laeger, T.